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Osteokines and the vasculature: a review of the in vitro effects of osteocalcin, fibroblast growth factor-23 and lipocalin-2

Millar, Sophie A.; Anderson, Susan I.; O'Sullivan, Saoirse E.


Sophie A. Millar

Saoirse E. O'Sullivan


Bone-derived factors that demonstrate extra-skeletal functions, also termed osteokines, are fast becoming a highly interesting and focused area of cross-disciplinary endocrine research. Osteocalcin (OCN), fibroblast growth factor-23 (FGF23) and lipocalin-2 (LCN-2), produced in bone, comprise an important endocrine system that is finely tuned with other organs to ensure homeostatic balance and health. This review aims to evaluate in vitro evidence of the direct involvement of these proteins in vascular cells and whether any causal roles in cardiovascular disease or inflammation can be supported. PubMed, Medline, Embase and Google Scholar were searched for relevant research articles investigating the exogenous addition of OCN, FGF23 or LCN-2 to vascular smooth muscle or endothelial cells. Overall, these osteokines are directly vasoactive across a range of human and animal vascular cells. Both OCN and FGF23 have anti-apoptotic properties and increase eNOS phosphorylation and nitric oxide production through Akt signalling in human endothelial cells. OCN improves intracellular insulin signalling and demonstrates protective effects against endoplasmic reticulum stress in murine and human endothelial cells. OCN may be involved in calcification but further research is warranted, while there is no evidence for a pro-calcific effect of FGF23 in vitro. FGF23 and LCN-2 increase proliferation in some cell types and increase and decrease reactive oxygen species generation, respectively. LCN-2 also has anti-apoptotic effects but may increase endoplasmic reticulum stress as well as have pro-inflammatory and pro-angiogenic properties in human vascular endothelial and smooth muscle cells. There is no strong evidence to support a pathological role of OCN or FGF23 in the vasculature based on these findings. In contrast, they may in fact support normal endothelial functioning, vascular homeostasis and vasodilation. No studies examined whether OCN or FGF23 may have a role in vascular inflammation. Limited studies with LCN-2 indicate a pro-inflammatory and possible pathological role in the vasculature but further mechanistic data is required. Overall, these osteokines pose intriguing functions which should be investigated comprehensively to assess their relevance to cardiovascular disease and health in humans.


Millar, S. A., Anderson, S. I., & O'Sullivan, S. E. (2019). Osteokines and the vasculature: a review of the in vitro effects of osteocalcin, fibroblast growth factor-23 and lipocalin-2. PeerJ, 7,

Journal Article Type Article
Acceptance Date May 17, 2019
Online Publication Date Jul 24, 2019
Publication Date Jul 24, 2019
Deposit Date May 24, 2019
Publicly Available Date May 24, 2019
Journal PeerJ
Electronic ISSN 2167-8359
Publisher PeerJ
Peer Reviewed Peer Reviewed
Volume 7
Article Number e7139
Keywords General Biochemistry, Genetics and Molecular Biology; General Neuroscience; General Agricultural and Biological Sciences; General Medicine
Public URL
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